Jagdeep Obhrai, MD, is a nephrologist who is focused on improving the lives of people who receive solid organ transplants. This proposal outlines a 5-year training program designed to enhance Dr. Obhrai's use of genetic techniques to study the early events that lead to transplant rejection. His primary mentor for this project, John lacomini, an Associate Professor at Brigham and Women's Hospital, is recognized as a leader in the use of these methods. His co-sponsor for the project, Mohamed Sayegh, is director of the Transplantation Research Center at Brigham and Women's Hospital, has experience generating and characterizing transgenic animals, and has mentored numerous junior investigators. The External Advisory Committee assembled for this project includes experts in mouse genetics and antigen presentation in alloimmunity. In immunology overall, it is recognized that activation of the immune system by non-antigenic factors is necessary for generation of immune responses. This paradigm has not been established in alloimmunity. This research project focuses on understanding which non-antigenic factors are required to initiate alloimmune response. This will be done by creating a novel mouse model that allow drug-induced expression of alloantigen on cardiac tissues independent of surgical transplantation (Aim 1). Using this model, Dr. Obhrai will study how the expression of alloantigen on parenchymal or vascular tissue affects the generation of immune injury. This work will also define which T cells cause the initial injury to the transplanted organ (Aim 2). He will also examine how ischemia-reperfusion injury and tissue damage impact the development of immune-mediate allograft injury (Aim 3). The Transplantation Research Center at Brigham and Women's Hospital is an ideal setting for Jagdeep Obhrai's training and the conduct of this project. The Center brings together investigators with diverse expertise who are focused on the science of transplantation to improve the lives of transplant recipients.